We recently demonstrated that delivery of physiological amounts of microRNA-145 (miR-145) completely restored impaired coronary collateral growth (CCG) in a rat model of metabolic syndrome by restoring vascular smooth muscle cells (VSMCs) to their normal physiological phenotype (contractile vs. synthetic) in the late stage of CCG. miR-145 is highly enriched in smooth muscle and is expressed at high levels in normal, healthy coronary VSMCs. Its expression is severely decreased in VSMCs of metabolic syndrome animals and humans and correlates with loss of the normal contractile VSMC phenotype. As such this intervention has potentially important implications for clinical re-vascularization therapy. However, to assess the clinical applicability of miR-145-based therapy for induction of CCG, it is essential to understand the mechanisms by which it achieved restoration of CCG. We propose that this single miR delivered to a single cell type (VSMC) had such a profound effect on a complex process of collateral growth, which involves coordinated interactions between multiple cell types, because the miR-145-induced conversion of synthetic VSMCs to contractile VSMCs in turn modulated all key regulatory aspects of CCG including ECM remodeling, endothelial cell (EC) survival and function, inflammatory cell infiltration, and reactive oxygen species (ROS), bioavailability of growth factors vs. growth inhibitors, and nitric oxide (NO). Our data show that VSMC-specific miR-145 delivery converted VSMCs from synthetic to contractile phenotype and normalized (converted to profile seen in normal animals) ECM composition, inflammation, including cytokine, ROS and MMP levels, and endothelial function in the metabolic syndrome animals. In contrast, delivery of the biological inhibitor of miR-145 (antimiR-145) to the normal animals resulted in induction of the synthetic VSMC phenotype, which produced the ECM composition, inflammatory profile, ROS and MMP production, and endothelial dysfunction similar to that observed in JCR rats. Therefore, we hypothesize that restoration of physiological VSMC miR-145 levels in the late stage of CCG in the metabolic syndrome restores CCG by normalizing ECM composition and inflammation and restoring endothelial function.
Three specific aims will be addressed: 1) determine whether VSMC-specific miR-145 delivery normalizes ECM remodeling during CCG in the metabolic syndrome, 2) determine whether VSMC-specific miR-145 delivery and normalized ECM remodeling ameliorate excessive inflammation (inflammatory cell infiltration, cytokine, ROS and MMP production from these cells) during CCG in the metabolic syndrome, and 3) determine whether VSMC-specific miR-145 delivery and normalized ECM remodeling restore endothelial function during CCG in the metabolic syndrome. These in vivo studies will identify functional physiological responses, which account for miR-145's global effect on CCG recovery, at the cellular level.

Public Health Relevance

People with metabolic syndrome are at high risk for heart attacks, in part because they fail to grow collateral vessels in response to stable angina (chest pain). We have recently used a small RNA molecule (microRNA) to successfully stimulate collateral vessel growth in a rat model of metabolic syndrome. This intervention has high potential for prevention of heart attacks in humans, but the mechanisms by which this microRNA was able to induce collateral growth must first be understood. This is the goal of this proposal.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL093052-08S1
Application #
9322694
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Hasan, Ahmed AK
Project Start
2017-01-13
Project End
2019-03-31
Budget Start
2017-01-13
Budget End
2017-03-31
Support Year
8
Fiscal Year
2017
Total Cost
$20,240
Indirect Cost
$7,040
Name
New York Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Rocic, Petra; Schwartzman, Michal Laniado (2018) 20-HETE in the regulation of vascular and cardiac function. Pharmacol Ther 192:74-87
Soler, Amanda; Hunter, Ian; Joseph, Gregory et al. (2018) Elevated 20-HETE in metabolic syndrome regulates arterial stiffness and systolic hypertension via MMP12 activation. J Mol Cell Cardiol 117:88-99
Rocic, Petra (2017) Can microRNAs be Biomarkers or Targets for Therapy of Ischemic Coronary Artery Disease in Metabolic Syndrome? Curr Drug Targets 18:1722-1732
Joseph, Gregory; Soler, Amanda; Hutcheson, Rebecca et al. (2017) Elevated 20-HETE impairs coronary collateral growth in metabolic syndrome via endothelial dysfunction. Am J Physiol Heart Circ Physiol 312:H528-H540
Hunter, Ian; Soler, Amanda; Joseph, Gregory et al. (2017) Cardiovascular function in male and female JCR:LA-cp rats: effect of high-fat/high-sucrose diet. Am J Physiol Heart Circ Physiol 312:H742-H751
Diane, Abdoulaye; Pierce, W David; Kelly, Sandra E et al. (2016) Mechanisms of Comorbidities Associated With the Metabolic Syndrome: Insights from the JCR:LA-cp Corpulent Rat Strain. Front Nutr 3:44
Rocic, Petra (2015) Can ErbB2 overexpression protect against doxorubicin cardiotoxicity? Am J Physiol Heart Circ Physiol 309:H1235-6
Hutcheson, Rebecca; Terry, Russell; Hutcheson, Brenda et al. (2015) miR-21-mediated decreased neutrophil apoptosis is a determinant of impaired coronary collateral growth in metabolic syndrome. Am J Physiol Heart Circ Physiol 308:H1323-35
Hutcheson, Rebecca; Chaplin, Jennifer; Hutcheson, Brenda et al. (2014) miR-21 normalizes vascular smooth muscle proliferation and improves coronary collateral growth in metabolic syndrome. FASEB J 28:4088-99
Villalta, Patricia C; Rocic, Petra; Townsley, Mary I (2014) Role of MMP2 and MMP9 in TRPV4-induced lung injury. Am J Physiol Lung Cell Mol Physiol 307:L652-9

Showing the most recent 10 out of 19 publications